Tissue injury initiates a scarring process involving stromal cell activation and expansion. Initially beneficial, persistent stromal cell activation and proliferation generate pro-fibrotic cells and accumulation of extracellular matrix, which compromises organ recovery. Inflammation is an important initiator of the fibrosis but the cellular origin of pro-fibrotic stromal cells and their mechanism of activation remain unclear.
During inflammation, stromal cells regulate lymphocyte recruitment and survival through the secretion of specific chemokines and cytokines, resulting eventually in the clearance of inflammation, this phase is usually named the acute phase of inflammation. Disruption of this homeostasis can lead to chronic inflammation and its corollary of severe illnesses, such as tissue fibrosis.
Fibrosis is the formation of excess fibrous connective tissue during the reparative and reactive process following tissue damage and inflammation. As major components of fibrosis, pro-fibrotic stromal cells play a critical role in the maintenance of chronic inflammation and often preclude full organ recovery, and in some cases can induce organ failure. This can lead to severe illnesses of major impact on public health such as liver cirrhosis, scleroderma, heart and pulmonary fibrosis, atherosclerosis, and asthma. The formation of tissue fibrosis is currently considered to be an irreversible process, which is poorly modulated by anti-inflammatory and immunosuppressive drugs. The mechanisms leading to the formation of tissue fibrosis has remained elusive and therefore has prevented the elaboration of an adequate therapeutic treatment.
The inventors have described previously the emergence of a stromal population of cells (gp38+ lymphoid stromal cells) that massively proliferate and provide key survival, chemotactic and morphogenic factors for the development of lymphocyte permissive tissue during ontogeny and inflammation (Peduto et al., Journal of Immunology, 2009, 182:5789-5799). They have shown that these stromal cells are not recruited from circulating precursors but develop from tissue-resident cells that remained to be characterized.
ADAMs (A Disintegrin And Metalloproteinase) are a family of cell surface multidomain proteins having key roles in the ectodomain shedding and processing of growth factors, cytokines, receptors, adhesion molecules and other molecules from the plasma membrane. This process has emerged as an important posttranslational regulator of the function of many cleaved substrate proteins, including EGF-receptor ligands and TNFα. In addition to protease activity, several ADAMs possess cell binding and cell signalling properties due to their non-catalytic domains. More than 30 members have been identified in the ADAM family with a broad tissue distribution and have been involved in several cellular processes. Due to their ability to rapidly affect key signalling activities between cells and their environment, ADAM family members could conceivably contribute to pathogenesis including tumorigenesis, especially if their function is dysregulated. Therefore, they are making up the majority of pharmaceutical targets currently undergoing preclinical and clinical evaluation (Moss et al., “ADAMs: Targets for Drug Discovery”, Current Pharmaceutical Design, 2009, 15(20):2270-1).
ADAM12 is an active protease involved in the Epidermal Growth Factor Receptor (EGFR) and insulin-like growth factor (IGF) receptor signalling, and plays a role in tumor progression (Peduto et al., Oncogene, 2006, 25:5462-5466). ADAM12 is also involved in several diseases such as arthrosis, cardiac hypertrophy and neurodegenerative diseases (Jacobsen & Wewer, Current Pharmaceutical Design, 2009, 15: 2300-2310).
There is still a need to provide tools, markers and inhibitors for inflammation induced fibrosis.